Nanoscience provides unprecedented possibilities in tackling incurable diseases like cancer. Merited in a wide variety of chemical flexibility and functional modularity, nanomaterials showed clinical potentials as novel diagnostic and therapeutic tools for cancer therapy. Even with the tremendous opportunities as for the next generation medicines, however, pharmacological mechanisms at a molecular level remains largely unresolved. Recently, metallofullerenol Gd@C82(OH)22 was shown to have considerable anti-tumoral efficacy in various cancer models (i.e., breast, liver, and pancreatic) genografted in mice. In experiments, Gd@C82(OH)22 targeted proteins relevant to cancer migration. Specifically, Gd@C82(OH)22 directly inhibited matrix metalloproteinases (i.e., MMP-2/9), elemental enzymes for angiogenesis and metastasis in cancer media, besides down-regulation of their mRNA and protein expressions. Furthermore, Gd@C82(OH)22 also inhibited protein association between histone deacetylase-1 (HDAC1) and metastasis-associated protein 1 (MTA1), as remotely down-regulating MMP expressions. We, then, applied large-scale molecular dynamics simulations in order to understand the protein-nanoparticle interactions in atomistic details. Our simulation reveals that Gd@C82(OH)22 can inhibit MMPs allosterically at the ligand-specificity S1’ loop rather than directly blocking the active site, but with different affinities between MMP2 and MMP9, as proposing distinctive inhibitory mechanisms in contrast to small molecular organic drugs. With HDAC1, Gd@C82(OH)22 effectively blocks sub-domains important to MTA1 association, consistently with experiments. Our results demonstrate how nanoparticles can function as a potential “nanodrug”, and also provides an intuition on how they are different from the conventional ones.

In silico modeling of nanodrug: Molecular insight of metallofullerenol Gd@C82(OH)22 in cancer anti-metastasis

254th National Meeting (2017)

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